Gerd Fastner

Recommendations for standardized pathological characterization of residual disease for neoadjuvant clinical trials of breast cancer by the BIG-NABCG collaboration

Neoadjuvant systemic therapy (NAST) provides the unique opportunity to assess response to treatment after months rather than years of follow-up. However, significant variability exists in methods of pathologic assessment of response to NAST, and thus its interpretation for subsequent clinical decisions. Our international multidisciplinary working group was convened by the Breast International Group-North American Breast Cancer Group (BIG-NABCG) collaboration and tasked to recommend practical methods for standardized evaluation of the post-NAST surgical breast cancer specimen for clinical trials that promote accurate and reliable designation of pathologic complete response (pCR) and meaningful characterization of residual disease. Recommendations include multidisciplinary communication; clinical marking of the tumor site (clips); and radiologic, photographic, or pictorial imaging of the sliced specimen, to map the tissue sections and reconcile macroscopic and microscopic findings. The information required to define pCR (ypT0/is ypN0 or ypT0 yp N0), residual ypT and ypN stage using the current AJCC/UICC system, and the Residual Cancer Burden system were recommended for quantification of residual disease in clinical trials.

A Dosimetric Comparison of IORT Techniques in Limited-Stage Breast Cancer

Background and Purpose:For intraoperative radiotherapy (IORT) during breast-conserving treatment four different techniques have been addressed: interstitial brachytherapy, an inflatable balloon with a central high-dose-rate source (MammoSite), a miniature orthovolt system (Intrabeam), and linac-based electron radiotherapy (IOERT). The dosimetric properties of these methods are compared.Material and Methods:Planning target volumes (PTVs) of the same size but of different shapes are assumed, corresponding to the technique’s specific situs. Dose distributions for the PTVs and for surrounding tissues are demonstrated by dose-volume histograms and a list of physical parameters. A dose inhomogeneity index (DII) is introduced to describe the deviation of a delivered from the prescribed dose, reaching its minimal value 0 in case of perfect homogeneity.Results:In terms of DII, IOERT reaches the lowest value followed by the MammoSite, the Intrabeam and interstitial implants. The surrounding tissues receive the smallest average dose with IOERT, closely followed by the orthovolt system.Conclusion:When comparing simplified geometric figures, IOERT delivers the most homogeneous dose distributions. However, in clinical reality PTVs often present asymmetric shapes instead of ideal geometries. Due to a strictly centric dose fall-off, any system with a round central applicator will have technical limits. During IOERT margin-directed applicator guidance is possible and interstitial brachytherapy allows for polygonal dose shaping. These techniques seem to be superior for asymmetric PTV irradiation.Hintergrund und Ziel:Für die intraoperative Radiotherapie (IORT) des konservativ operierten Mammakarzinoms sind vier Techniken in Gebrauch: die interstitielle Brachytherapie, ein aufblasbarer Ballon mit einer zentralen High-Dose-Rate-Quelle (Mammo-Site), ein Miniatur-Orthovoltsystem (Intrabeam) sowie Elektronen am Linac (IOERT). Die dosimetrischen Eigenschaften dieser Methoden werden verglichen.Material und Methodik:Für jede dieser Techniken werden Planungszielvolumina (PTVs) des gleichen Volumens, aber unterschiedlicher Form angenommen, die dem jeweiligen typischen Situs zum Zeitpunkt der Applikation entsprechen (Abbildung 1, Tabellen 1 und 2). Die Dosisverteilungen (Abbildung 2) inner- und außerhalb der PTVs werden mittels Dosis-Volumen-Histogrammen und einer Reihe von Parametern miteinander verglichen (Abbildung 3, Tabelle 3). Ein Dosisinhomogenitätsindex (DII) wird vorgestellt, der die Abweichung einer verabreichten von einer vorgeschriebenen Dosis beschreibt und im Fall einer perfekten Homogenität den Minimalwert 0 erreicht.Ergebnisse:In Bezug auf den DII erreicht die IOERT den niedrigsten Wert, gefolgt von MammoSite, dem Orthovoltsystem und den interstitiellen Implantaten. Das umgebende Gewebe erhält die geringste mittlere Dosis mittels IOERT, knapp gefolgt vom Intrabeam (Abbildung 3, Tabelle 3).Schlussfolgerung:Die IOERT zeigt die homogenste Dosisverteilung. In der klinischen Realität weisen PTVs aber häufig asymmetrische anstelle idealgeometrischer Formen auf. Durch den strikten zentralen Dosisabfall bestehen bei Systemen mit runden zentralen Applikatoren technische Limitationen. Während einer IOERT ist eine asymmetrische Applikatorführung möglich, die interstitielle Brachytherapie erlaubt eine polygonale Dosisformung, weshalb diese beiden Verfahren zur Erfassung asymmetrischer PTVs überlegen scheinen (Abbildung 4).

IORT with electrons as boost strategy during breast conserving therapy in limited stage breast cancer: Long term results of an ISIORT pooled analysis

PURPOSE Linac-based intraoperative radiotherapy with electrons (IOERT) was implemented to prevent local recurrences after breast conserving therapy (BCT) and was delivered as an intraoperative boost to the tumor bed prior to whole breast radiotherapy (WBI). A collaborative analysis has been performed by European ISIORT member institutions for long term evaluation of this strategy. MATERIAL AND METHODS Until 10/2005, 1109 unselected patients of any risk group have been identified among seven centers using identical methods, sequencing and dosage for intra- and postoperative radiotherapy. A median IOERT dose of 10 Gy was applied (90% reference isodose), preceding WBI with 50-54 Gy (single doses 1.7-2 Gy). RESULTS At a median follow up of 72.4 months (0.8-239), only 16 in-breast recurrences were observed, yielding a local tumor control rate of 99.2%. Relapses occurred 12.5-151 months after primary treatment. In multivariate analysis only grade 3 reached significance (p=0.031) to be predictive for local recurrence development. Taking into account patient age, annual in-breast recurrence rates amounted 0.64%, 0.34%, 0.21% and 0.16% in patients <40 years; 40-49 years; 50-59 years and ≥ 60 years, respectively. CONCLUSION In all risk subgroups, a 10 Gy IOERT boost prior to WBI provided outstanding local control rates, comparing favourably to all trials with similar length of follow up.

Preoperative Oxaliplatin, Capecitabine, and External Beam Radiotherapy in Patients with Newly Diagnosed, Primary Operable, cT3NxM0, Low Rectal Cancer

AbstractPurpose:In patients with locally advanced rectal cancer (LARC), preoperative chemoradiation is known to improve local control, and down-staging of the tumor serves as a surrogate for survival. Intensification of the systemic therapy may lead to higher downstaging rates and, thus, enhance survival. This phase II study investigated the efficacy and safety of preoperative capecitabine and oxaliplatin in combination with radiotherapy.Patients and Methods:Patients with LARC of the mid and lower rectum, T3NxM0 staged by MRI received radiotherapy (total dose 45 Gy) in combination with oral capecitabine (825 mg/m2 twice a day on radiotherapy days; weeks 1–4) and oxaliplatin 50 mg/m2 intravenously (days 1, 8, 15, and 22). Efficacy was evaluated as rate of tumor down-categorization at the T level.Results:A total of 59 patients were enrolled (19 women, 40 men; median age of 61 years) and all were evaluable for efficacy and toxicity. Down-categorization at the T level was observed in 53% with pathological complete response in 6 patients (10%). Actual total radiotherapy, oxaliplatin and capecitabine doses received were 97%, 90%, and 93% of the protocol-specified preplanned doses, respectively. Grade 3/4 toxicity was observed in 15 patients (25%). The most frequent was diarrhea (12%).Conclusions:Preoperative chemoradiation with capecitabine and oxaliplatin is feasible in patients with MRI-proven cT3 LARC. The only clinically relevant toxicity was diarrhea. Overall, efficacy of the multimodality treatment was good, but not markedly exceeding that of 5-FU- or capecitabine-based chemoradiation approaches.ZusammenfassungZiel:Eine präoperative Radiochemotherapie verbessert bei Patienten mit einem tief sitzenden Rektumkarzinom (LARC) die lokale Tumorkontrolle und ein so genanntes „down-staging“ dient als Überlebenssurrogatparameter. Von einer Dosisintensivierung der systemischen Therapie kann man sich höhere Down-Staging-Raten erwarten und damit das Überleben verbessern. Diese multizentrische Phase-II-Studie soll die Wirksamkeit und Toxizität einer neoadjuvanten durch Capecitabin und Oxaliplatin intensivierten Radiochemotherapie prüfen.Patienten und Methodik:Patienten mit einem LARC, das mittels MRI als cT3NxM0 klassifizierten wurde, erhielten eine Radiotherapie (45 Gy in konventioneller Fraktionierung) mit konkomitanter Gabe von Capecitabin (oral 2 x täglich 825 mg an den Bestrahlungstagen, Woche 1–4) und Oxaliplatin intravenös 50mg/m2 (an den Tagen 1, 8, 15 und 22). Die Rate an Tumor-Down- Categorization dient als Parameter der Wirksamkeit.Ergebnisse:59 Patienten (davon 68% männlich, mittleres Alter 61 Jahre) wurden in die Studie eingeschlossen. Eine Down- Categorization in der T-Kategorie wurde in 53% der Patienten beobachtet, wobei 6 Patienten (10%) eine komplette pathologische Remission zeigten. Die tatsächlich verabreichte Strahlendosis betrug 97%, die Capecitabindosis 93% und die Oxaliplatindosis 90% der im Protokoll festgelegten Gesamtdosis. Akute Nebenwirkungen CTC-Grad ≥3 (Common Toxicity Criteria) wurden in 15 Patienten (25%) registriert, wobei mit 12% eine Diarrhoe am häufigsten vorkam.Schlussfolgerung:Eine präoperative Radiochemotherapie mit Capecitabin und Oxaliplatin ist bei Patienten mit mittels MRI diagnostiziertem cT3 LARC gut durchführbar. Die einzige klinisch relevante Nebenwirkung war eine Diarrhoe. Allerdings übertrifft die Wirksamkeit nicht wesentlich die bisherigen Erkenntnisse von Studien mit kontinuierlicher 5-Fluorouracil- oder alleiniger Capecitabingabe.

“Augmented Reality” in Conventional Simulation by Projection of 3-D Structures into 2-D Images

Background and Purpose:In this study, a new method is introduced, which allows the overlay of three-dimensional structures, that have been delineated on transverse slices, onto the fluoroscopy from conventional simulators in real time.Patients and Methods:Setup deviations between volumetric imaging and simulation were visualized, measured and corrected for 701 patient isocenters.Results:Comparing the accuracy to mere virtual simulation lacking additional X-ray imaging, a clear benefit of the new method could be shown. On average, virtual prostate simulations had to be corrected by 0.48 cm (standard deviation [SD] 0.38), and those of the breast by 0.67 cm (SD 0.66).Conclusion:The presented method provides an easy way to determine entity-specific safety margins related to patient setup errors upon registration of bony anatomy (prostate 0.9 cm for 90% of cases, breast 1.3 cm). The important role of planar X-ray imaging was clearly demonstrated. The innovation can also be applied to adaptive image-guided radiotherapy (IGRT) protocols.Hintergrund und Ziel:Es wird ein Verfahren vorgestellt, das die Einblendung von dreidimensionalen Strukturen, die zuvor z.B. auf axialen Schnittbildern segmentiert wurden, in Durchleuchtungsaufnahmen am konventionellen Simulator in Echtzeit erlaubt.Patienten und Methodik:Mit dieser Technologie wurden an 701 Patientenisozentren Lagerungsunterschiede zwischen der Schnittbildgebung und der Simulation visualisiert, vermessen und korrigiert.Ergebnisse:Im Vergleich der Genauigkeit mit der rein virtuellen Simulation, bei der auf Röntgenbildgebung verzichtet wird, zeigte sich eine deutliche Überlegenheit der neuen Methode. Im Mittel wurden virtuell simulierte Prostatabestrahlungen um 0,48 cm (Standardabweichung [SD] 0,38) und jene der Mamma um 0,67 cm (SD 0,66) korrigiert.Schlussfolgerung:Das vorgestellte Verfahren erlaubt die einfache Bestimmung entitätsspezifischer Sicherheitsränder für Lagerungsungenauigkeiten von knöchernen Strukturen (Prostatabestrahlung 0,9 cm für 90% der Fälle, Mamma 1,3 cm; Tabelle 2). Die Bedeutung von planarer kV-Bildgebung konnte gezeigt werden. Das innovative Verfahren ist auch im Rahmen von Protokollen zur adaptiven, bildgeführten Radiotherapie (IGRT) einsetzbar.

Augmented reality in conventional simulation by projection of 3-D structures into 2-D images: a comparison with virtual methods.

Background and Purpose:In this study, a new method is introduced, which allows the overlay of three-dimensional structures, that have been delineated on transverse slices, onto the fluoroscopy from conventional simulators in real time.Patients and Methods:Setup deviations between volumetric imaging and simulation were visualized, measured and corrected for 701 patient isocenters.Results:Comparing the accuracy to mere virtual simulation lacking additional X-ray imaging, a clear benefit of the new method could be shown. On average, virtual prostate simulations had to be corrected by 0.48 cm (standard deviation [SD] 0.38), and those of the breast by 0.67 cm (SD 0.66).Conclusion:The presented method provides an easy way to determine entity-specific safety margins related to patient setup errors upon registration of bony anatomy (prostate 0.9 cm for 90% of cases, breast 1.3 cm). The important role of planar X-ray imaging was clearly demonstrated. The innovation can also be applied to adaptive image-guided radiotherapy (IGRT) protocols.Hintergrund und Ziel:Es wird ein Verfahren vorgestellt, das die Einblendung von dreidimensionalen Strukturen, die zuvor z.B. auf axialen Schnittbildern segmentiert wurden, in Durchleuchtungsaufnahmen am konventionellen Simulator in Echtzeit erlaubt.Patienten und Methodik:Mit dieser Technologie wurden an 701 Patientenisozentren Lagerungsunterschiede zwischen der Schnittbildgebung und der Simulation visualisiert, vermessen und korrigiert.Ergebnisse:Im Vergleich der Genauigkeit mit der rein virtuellen Simulation, bei der auf Röntgenbildgebung verzichtet wird, zeigte sich eine deutliche Überlegenheit der neuen Methode. Im Mittel wurden virtuell simulierte Prostatabestrahlungen um 0,48 cm (Standardabweichung [SD] 0,38) und jene der Mamma um 0,67 cm (SD 0,66) korrigiert.Schlussfolgerung:Das vorgestellte Verfahren erlaubt die einfache Bestimmung entitätsspezifischer Sicherheitsränder für Lagerungsungenauigkeiten von knöchernen Strukturen (Prostatabestrahlung 0,9 cm für 90% der Fälle, Mamma 1,3 cm; Tabelle 2). Die Bedeutung von planarer kV-Bildgebung konnte gezeigt werden. Das innovative Verfahren ist auch im Rahmen von Protokollen zur adaptiven, bildgeführten Radiotherapie (IGRT) einsetzbar.

Boost IORT in Breast Cancer: Body of Evidence

The term IORT (intraoperative radiotherapy) is currently used for various techniques that show decisive differences in dose delivery. The largest evidence for boost IORT preceding whole breast irradiation (WBI) originates from intraoperative electron treatments with single doses around 10 Gy, providing outstandingly low local recurrence rates in any risk constellation also at long term analyses. Compared to other boost methods, an intraoperative treatment has evident advantages as follows. Precision. Direct visualisation of the tumour bed during surgery guarantees an accurate dose delivery. This fact has additionally gained importance in times of primary reconstruction techniques after lumpectomy to optimise cosmetic outcome. IORT is performed before breast tissue is mobilised for plastic purposes. Cosmesis. As a consequence of direct tissue exposure without distension by hematoma/seroma, IORT allows for small treatment volumes and complete skin sparing, both having a positive effect on late tissue tolerance and, hence, cosmetic appearance. Patient Comfort. Boost IORT marginally prolongs the surgical procedure, while significantly shortening postoperative radiotherapy. Its combination with a 3-week hypofractionated external beam radiotherapy to the whole breast (WBI) is presently tested in the HIOB trial (hypofractionated WBI preceded by IORT electron boost), a prospective multicenter trial of the International Society of Intraoperative Radiotherapy (ISIORT).

Multi-institutional pooled analysis on adjuvant chemoradiation in pancreatic cancer

PURPOSE To determine the impact of chemoradiation therapy (CRT) on overall survival (OS) after resection of pancreatic adenocarcinoma. METHODS AND MATERIALS A multicenter retrospective review of 955 consecutive patients who underwent complete resection with macroscopically negative margins (R0-1) for invasive carcinoma (T1-4; N0-1; M0) of the pancreas was performed. Exclusion criteria included metastatic or unresectable disease at surgery, macroscopic residual disease (R2), treatment with intraoperative radiation therapy (IORT), and a histological diagnosis of no ductal carcinoma, or postoperative death (within 60 days of surgery). In all, 623 patients received postoperative radiation therapy (RT), 575 patients received concurrent chemotherapy (CT), and 462 patients received adjuvant CT. RESULTS Median follow-up was 21.0 months. Median OS after adjuvant CRT was 39.9 versus 24.8 months after no adjuvant CRT (P<.001) and 27.8 months after CT alone (P<.001). Five-year OS was 41.2% versus 24.8% with and without postoperative CRT, respectively. The positive impact of CRT was confirmed by multivariate analysis (hazard ratio [HR] = 0.72; confidence interval [CI], 0.60-0.87; P=.001). Adverse prognostic factors identified by multivariate analysis included the following: R1 resection (HR = 1.17; CI = 1.07-1.28; P<.001), higher pT stage (HR = 1.23; CI = 1.11-1.37; P<.001), positive lymph nodes (HR = 1.27; CI = 1.15-1.41; P<.001), and tumor diameter >20 mm (HR = 1.14; CI = 1.05-1.23; P=.002). Multivariate analysis also showed a better prognosis in patients treated in centers with >10 pancreatic resections per year (HR = 0.87; CI = 0.78-0.97; P=.014) CONCLUSION: This study represents the largest comparative study on adjuvant therapy in patients after resection of carcinoma of the pancreas. Overall survival was better in patients who received adjuvant CRT.

Outcomes in a Multi-institutional Cohort of Patients Treated With Intraoperative Radiation Therapy for Advanced or Recurrent Renal Cell Carcinoma

PURPOSE/OBJECTIVE(S) This study aimed to analyze outcomes in a multi-institutional cohort of patients with advanced or recurrent renal cell carcinoma (RCC) who were treated with intraoperative radiation therapy (IORT). METHODS AND MATERIALS Between 1985 and 2010, 98 patients received IORT for advanced or locally recurrent RCC at 9 institutions. The median follow-up time for surviving patients was 3.5 years. Overall survival (OS), disease-specific survival (DSS), and disease-free survival (DFS) were estimated with the Kaplan-Meier method. Chained imputation accounted for missing data, and multivariate Cox hazards regression tested significance. RESULTS IORT was delivered during nephrectomy for advanced disease (28%) or during resection of locally recurrent RCC in the renal fossa (72%). Sixty-nine percent of the patients were male, and the median age was 58 years. At the time of primary resection, the T stages were as follows: 17% T1, 12% T2, 55% T3, and 16% T4. Eighty-seven percent of the patients had a visibly complete resection of tumor. Preoperative or postoperative external beam radiation therapy was administered to 27% and 35% of patients, respectively. The 5-year OS was 37% for advanced disease and 55% for locally recurrent disease. The respective 5-year DSS was 41% and 60%. The respective 5-year DFS was 39% and 52%. Initial nodal involvement (hazard ratio [HR] 2.9-3.6, P<.01), presence of sarcomatoid features (HR 3.7-6.9, P<.05), and higher IORT dose (HR 1.3, P<.001) were statistically significantly associated with decreased survival. Adjuvant systemic therapy was associated with decreased DSS (HR 2.4, P=.03). For locally recurrent tumors, positive margin status (HR 2.6, P=.01) was associated with decreased OS. CONCLUSIONS We report the largest known cohort of patients with RCC managed by IORT and have identified several factors associated with survival. The outcomes for patients receiving IORT in the setting of local recurrence compare favorably to similar cohorts treated by local resection alone suggesting the potential for improved DFS with IORT.

ISIORT pooled analysis 2013 update: clinical and technical characteristics of intraoperative radiotherapy

Purpose: Data from centers active in intraoperative radiotherapy (IORT) were collected within the International Society of Intraoperative Radiation Therapy (ISIORT)-Europe program. The purpose of the present study was to analyze and report the main clinical and technical variables of IORT performed by the participating centers. Materials and methods: Since 2007, ISIORT-Europe centers were invited to record data of IORT procedures in a common database. Other centers worldwide joined this initiative over time. Collected data included demographic, clinical and technical information. Results: Thirty-one centers participated in the survey and data of 7,196 IORT procedures have been recorded to 2013. Median age of patients was 60.6 years (range 5 months-94 years). Gender was female in 80.2% of cases and male in 19.8%. Treatment intent was curative in 7,054 cases (98%) and 1,587 patients (22.1%) were included in study protocols. The most frequent tumor was breast cancer with 5,654 cases (78.6%) followed by rectal cancer with 641 cases (8.9%), soft-tissue and bone sarcoma with 257 cases (3.6%), prostate cancer with 128 cases (1.8%), pancreatic cancer with 87 cases (1.2%), gastric cancer with 65 cases (0.9%), and esophageal cancer with 53 cases (0.7%). Treatment chronology shows how IORT number of recorded cases increased according with the interest in the ISIORT project. C onclusions: This report gives an overview of patient selection and treatment modalities for the main tumor types effectively treated in a large group of active and experienced international centers using IORT. This data can be a basis for further surveys and for prospective studies devoted to analyze in depth IORT containing multimodal cancer treatment approaches.